Pharmaceutical Composition Containing Glimepiride and Metformin Hydrochloride

ABSTRACT

Pharmaceutical compositions of the active substances glimepiride with metformin or its salts such as hydrochloride, succinate, fumarate, etc. are useful to control blood glucose in patients with type 2 diabetes. To prove the effectiveness of the combination, clinical studies were conducted that demonstrated the existence of not only an additive effect, but also a synergistic effect of the two drugs compared with monotherapy using only one of the drugs used in combination. In consequence, the combination may be used as an effective and safe therapy to control blood glucose in patients with type 2 diabetes, using different proportions of the active substances in combinations suitable for the needs of different patients.

FIELD OF THE INVENTION

This invention consists of providing a therapeutic combinationconsisting of the sulfonylurea glimepiride and the biguanide metformin,both oral hypoglycemics, which, when combined, produce not only anadditive effect but also a synergistic effect and therefore greatereffectiveness in controlling blood glucose levels in patients with type2 diabetes.

BACKGROUND

The use of sulfonylureas in treating type 2 diabetes is fullyestablished as an effective means of controlling hypoglycemia. At themolecular level, sulfonylureas act on the receptor in β pancreatic cellsknown as SUR, which, when it is activated, closes an ATP dependentpotassium channel, which in turn causes a reduction in potassium intakeand in consequence depolarization of the membrane. This in turn causesan increase in the flow of calcium toward the cell's interior,activating the cytoskeleton, which causes translocation of secretorygranules, thereby releasing insulin by exocytosis.

Another treatment whose use has spread recently is with the biguanidemetformin, which acts effectively not only to control hypoglycemia, butalso in its prevention. Metformin has a different mechanism of actionfrom sulfonylureas, increasing insulin sensitivity in hepatic andperipheral tissue (mainly muscular tissues). Metformin inhibitsgluconeogenesis and hepatic glycogenolysis. At the cellular level,heightened insulin sensitivity is explained by the increased activity itinduces in the tyrosin kinase post-receptor and the resulting increasein the number and activity of GLUT4 transporters.

However, around 75% of type 2 diabetes patients treated withsulfonylureas do not succeed in bringing their glucose level to thedesired values, and need to complement their treatment with a secondoral agent. Also, most patients with single drug treatment usingsulfonylureas after a certain number of years require an additional drugthat contributes to their control therapy in order to achieve a suitablelevel of glycemic control. This loss of effectiveness is attributed tovarious causes, which are not yet well established, such as thesupposition that gradual deterioration of the pancreas renders it unableto maintain an exacerbated insulin excretion rate for a long period oftime due to constant, long-term stimulation caused by sulfonylureatherapy. However, contrary to this explanation, metformin therapy, whichdoes not act by over stimulating β cells, also presents lack of responseafter prolonged use, which would be contradictory to the explanationgiven for the lack of response of sulfonylureas.

On the other hand it has been found that combining sulfonylurea andmetformin therapy is more effective than monotherapy with either of thetwo medications. Thus, it has been fully proven that the hypoglycemicaction of metformin is completely additional to that of sulfonylureas(de Fronzo, R. A. and Goodman, A. M. Yn, England J. Med. 333:541(1995)).

It also has been reported that when monotherapy with sulfonylureas doesnot achieve the desired levels it should not be discontinued andreplaced by metformin monotherapy, as this will not lower glucose levelsin plasma below the values observed with sulfonylurea monotherapy(Rosenstock, J. et al., Diabetes Care 19:1994 (1996); (Gasber, A. J., etal., Amer. J. Med. 103:491 (1997)).

It is generally recognized that, because diabetes mellitus is aprogressive disease, patients with good initial response to oral agentswill eventually require a second medication to achieve the desiredglycemic control. As we have mentioned, adding metformin to sulfonylureatherapy or vice-versa produces an additive response, not only to thereduction in glucose, but also to the reduction in lipids (Hermann, L.S., et al., Diabetes Care, 17:1100 (1994)).

There are several reports on the combined use of the sulfonylureaglibenclamide with the biguanide metformin. See, e.g., WO 97/17975;Vigneri et al., Diabetes and Metabolism, 17:232-234 (1991); Higginbothamet al., Med. J. Austr., 154-156 (1979); U.S. Pat. No. 6,303,146; and WO01/32,158.

Furthermore, there are several references on the combined use of thesulfonylurea glipizide with metformin. See, e.g., Cefalu et al.,Diabetes, 45 (Supl. 2):201A (1996); Croase et al., Circulation, 94 Supl1508 (1996); and Cefalu et al., Diabetology, 39 (Supl. 1): A231 (1996).

It has been reported that there are no great differences in efficacyamong various sulfonylureas (R. A. De Fronzo, Annals of InternalMedicine, 131:281-303 (1999)); S. Dagogo-Jack, et al., Archives InternalMedicine, 157:1802-1817 (1997); A. J. Scheen et al., Drugs 55:225-236(1998); R. Bressler et al., Archives Internal Medicine, 157:836-848(1997). Other reports indicate that glimepiride shows a potency twotimes higher than that of glibenclamide (R. Groomis et al.,Endocrinology, 13:117-121 (2000)). Moreover, in contrast toglibenclamide, chronic treatment of type 2 diabetic patients withglimepiride will not impair the vasodilator function of K_(ATP) openingin vivo (E. J. Abbink et al., Diabetic Medicine, 19:136-143 (2002).Furthermore, a lower incidence of severe hypoglycemia was reported intype 2 diabetic patients treated with glimepiride versus glibenclamide(A. Holstein et al. Diabetologia, 157:A40 (2000). Finally, Kramer etal., Biochimica et Biphysica Acta 1191:276-290 (1999)), reported thatglimepiride acts on a different receptor site on the β-cell than doesglibenclamide, and that glimepiride interacts with the β-cell receptorfor less time. Unlike glibenclamide, glimepiride seems to work in partby enhancing both the sensitivity and responsiveness of peripheraltissue to insulin (J. Sato et al. Excerpta Medica, 341-348 (1994), G. E.Sonnenberg et al., Annales Pharmaceuticals, 31:671-676 (1997)).

DESCRIPTION OF THE INVENTION

Combined glimepiride and metformin have been suggested previously in theliterature (G. Charpentier et al. Diabetic Medicine 18:828-834 (2001)).However, very little data is provided on its advantages or appropriatedosages. The prescribing information for the drug Amaryl (which activeingredient is glimepiride) warns of its supposed risk of hypoglycemiadue to concomitant use metformin (Physicians Desk Reference, 54 Edition,2000, page 1349). Thus, the current state of the art does not suggestthe development and use of a pharmaceutical composition combiningglimepiride and metformin, which in the present invention has been foundto offer unexpected advantages.

With the present invention we have performed clinical studies whichindicate that a pharmaceutical composition comprising a combination ofglimepiride and metformin in determined fixed ratios decreased theglycosylated haemoglobin (HbA_(1c)) in a synergistic way compared tousing glimepiride and metformin separately (Gonzalez-Ortiz et al., Rev.Inv. Clin. 56, in press, 2004). That is, the combined use of both drugsin certain ratios displays a synergistic effect on the efficacy greaterthan the additive efficacy of glimepiride and metformin used separately.This synergistic effect, beside being manifested in the control ofglycosylated haemoglobin (HbA_(1c)), also controls fasting blood glucose(FBG) and post-prandial blood glucose (PPBG).

WO 00/40233 describes a pharmaceutical composition of glimepiride andmetformin. However, this composition is designed to deliver an initialconcentration of glimepiride, and later a delayed delivery of metformin.By this way of delivering both components it is not possible to maintainan appropriate bioavailability of the combined use of glimepiride andmetformin to achieve a synergistic effect.

In the clinical studies performed concerning the present invention, ithas been found that in order to obtain a pharmaceutical synergy, theratio between metformin/glimepiride must be maintained in the rangebetween about 500/1 to about 500/2 and using the appropriate dosage ofmetformin/glimepiride of 500/1, 500/2, 1000/2, 1000/4 (mg/mg),preferably 1000/2 mg/mg using a single dosage in a single tabletcontaining both drugs with 250 ml of water. After 10 hr of fasting in 16healthy volunteers, 8 men and 8 women, the plasma concentrations ofglimepiride was C_(max)=194.43+/−63.51 ng/ml and for metformin2245.16+/−580.91 ng/ml in a time of 1.98+/1−0.59 his and 1.56+/−0.56hrs, respectively. The half life of glimepiride was 3.73+/−1.28 hours,and of metformin was 2.62+/−0.33 hours. Using these conditions and thementioned ratio of glimepiride and metformin a synergistic control wasobserved in the glycosylated hemoglobin (HbA_(1c)), in the control offasting blood glucose (FBG), and in the post-prandial blood glucose(PPBG).

The great inconvenience of the pharmaceutical composition described inthe above mentioned patent WO 00/40233 A is that there is an initial andtotal delivery of glimepiride followed by a delayed delivery ofmetformin. Taking into account the short half life of glimepiride(around 3.73 hours), when the metformin starts delivering theglimepiride concentration in the blood will be falling such that therewill be a variable proportion of both drugs in the blood as a functionof time. After a longer period of time, the glimepiride will be clearedfrom the blood and only the delayed metformin will persist. The neteffect is a sequential medication of glimepiride alone followed by acombined medication of glimepiride and metformin with variableconcentrations in the blood, followed by the supply of metformin alone.With this type of bioavailability, it will be impossible to observe anysynergistic effect of the combination of both drugs.

The purpose of this invention is to provide a pharmaceutical compositionconsisting of glimepiride and metformin as its hydrochloride salt, orany other salt, and oral hypoglycemic therapy combining glimepiride andmetformin in a single fixed ratio that is more effective and just assafe as monotherapy with the same compounds in patients withuncontrolled type 2 diabetes mellitus.

To demonstrate the above, a random double blind clinical study wasconducted with a universe of 30 patients with uncontrolled type 2diabetes mellitus who receive monotherapy with sulfonylureas orbiguanides per group.

Criteria for inclusion were as follows:

1. Body mass index=27 kg/m²;

2. Age 40 to 65;

3. Capacity for deglutition; and

4 Voluntary consent

Criteria for exclusion were as follows:

1. Pregnancy;

2. Insulin treatment; and

3. Personal background of systemic diseases such as:

-   -   a) Cardiac insufficiency; and    -   b) Hepatic or chronic hepatopathic insufficiency.

4 Background of significant chronic complications with type 2 diabetesmellitus:

-   -   a) Renal insufficiency;    -   b) Ischemic cardiopathy;    -   c) Cerebral vascular disease; and    -   d) Visceral neuropathy.

5. Background of short-term terminal diseases, such as:

-   -   a) Cancer; and    -   b) HIV

6. Therapy with medications that present pharmacological interactionwith glimepiride or metformin, such as acetozolamide, nicotinic acid,para-aminosalicylic acid, non-steroidal anti-inflammatory analgesics,histamine antagonists 2, barbiturates, cyclophosamide, clonidine,cloranphenicol, cumarinics, disopyramide, epinephrine, estatines,fenfluramine, phenotiacine, fibrates, fluoxetine, guanitidine, steroidhormones, iphosamide, monoaminoxidase inhibitors, laxatives, miconazole,quinolones, reserpine, rifamicine, sulfamides, and tetracycline.

7. Known intolerance or allergies to sulfonylureas or biguanides.

Criteria for exclusion from the therapy, but not from the statisticalanalysis:

1. Presence of severe hypoglycemia at the maximum dosages used in thestudy;

2. Presence of severe hypoglycemia at the minimum dosages used in thestudy;

3. Presence of intolerable undesirable effects with any of themedications used in the study;

4. Failure to follow the medical treatment indicated;

5. Failure to attend scheduled visits;

6. Intercurrent illnesses or accidents that warrant hospitalization;

7. Administration during the study of medications with pharmacologicalinteraction with metformin or glimepiride; and

8. Voluntary withdrawal from the study.

The variables studied were as follows:

Dependent variables:

-   -   a) Glycemia between meals;    -   b) Glucosylated hemoglobin;    -   c) β-cell function;    -   d) Insulin resistance; and    -   e) Metabolic profile.

Independent variable:

-   -   a) Hypoglycemic therapy.

Intervening variables:

-   -   a) Age;    -   b) Sex;    -   c) Body mass index; and    -   d) Evolution of diabetes.

DEFINITIONS

Levels of glycemia between meals >139 mg/dL are defined as type 2diabetes mellitus.

Severe hypoglycemia: Glycemia between meals >260 mg/dL.

Severe hypoglycemia: Glycemia <60 mg/dL.

Non-adherence: Medication absorption <80%.

Absence: Missed appointment on >1 occasion.

Procedure

Identification, clinical history and selection of participants:

Clinical measurements and basal measurement of glycemia between meals,glucosylated hemoglobin, total cholesterol, cholesterol of high densitylipoproteins, triglycerides, creatinine, uric acid, glutemic-oxaloacetictransaminase, glutemic-pyruvic transaminase, lactic dehydrogenase,alkaline and insulin phosphatase.

Random assignment of patients to each group and pharmacologicalintervention in accordance with concentration of basal glycemia:

a) Glimepiride (2 mg tablets) Glycemia 140-180 mg/dl 1 mg ½ tabletGlycemia 181-220 mg/dl 2 mg 1 tablet Glycemia 221-260 mg/dl 4 mg 2tablets b) Metformin (1000 mg tablets) Glycemia 140-180 mg/dl 500 mg ½tablet Glycemia 181-220 mg/dl 1000 mg 1 tablet Glycemia 221-260 mg/dl2000 mg 2 tablets c) Glimepiride/Metformin ( 2/1000 mg tablets) 140-180mg/dl 1/500 mg ½ tablet

Clinical evaluation 30 and 60 days after beginning the study, measuringglycemia between meals and lactic dehydroginase.

Final clinical evaluations 90 days after the study begins, measuringglycemia between meals, glucosylated hemoglobin, total cholesterol, highdensity lipoprotein cholesterol, triglyceride, creatinine, uric acid,glutemic-oxaloacetic transaminase, glutemic-pyruvic transaminase, lacticdehydrogenase, alkaline and insulin phosphatase.

Undesirable effects were reported on a special record sheet, specifyingeach of the clinical manifestations considered probable, possible ordirectly related to the use of the drugs ingested.

The results obtained show that combined metformin and glimepiridetherapy was more effective in controlling glucosylated hemoglobinlevels, post-prandial blood glucose levels and blood glucose levelsbetween meals than single-drug treatment with glimepiride or metforminalone. The results obtained are shown below:

Combination glimepiride metformin Glucosylated hemoglobin HbA_(1c) −0.70+0.25 +0.06 Blood glucose between meals −1.77 +0.68 +0.75 Post-prandialblood glucose −2.7 +0.99 +1.08

What is extraordinary about the values obtained is that monotherapy witheither glimepiride or metformin has a similar effect in raising glucoselevels, while treatment with the combination clearly shows a beneficialeffect, which highlights its importance.

The previous combinations used in the clinical study can be illustratedby means of the following examples:

Example 1

A pharmaceutical composition is prepared consisting of 500 mg ofmetformin hydrochloride and 1 mg of glimepiride, adding the followingexcipients:

Microcrystalline Cellulose PH 101 39.20 mg Coloidal Silica Dioxide  1.80mg Povidone K-90 18.00 mg Croscarmelose Sodium 12.00 mg Magnesiumstereate  3.00 mg Clear Opadray YS-1-7006  5.00 mg Purified water 0.204mg

This pharmaceutical composition was used for the aforementioned clinicaltests.

Example 2

A pharmaceutical composition is prepared consisting of 500 mg ofmetformin hydrochloride and 2 mg of glimepiride, adding the followingexcipients:

Microcrystalline Cellulose PH 101 38.20 mg Coloidal Silica Dioxide  1.80mg Povidone K-90 18.00 mg Croscarmelose Sodium 12.00 mg Magnesiumstereate  3.00 mg Clear Opadray YS-1-7006  5.00 mg Purified water 0.204mg

This pharmaceutical composition was used for the aforementioned clinicaltests.

Example 3

A pharmaceutical composition is prepared consisting of 1000 mg ofmetformin hydrochloride and 2 mg of glimepiride, adding the followingexcipients:

Microcrystalline Cellulose PH 101 78.40 mg Coloidal Silica Dioxide 3.60mg Povidone K-90 36.00 mg Croscarmelose Sodium 24.00 mg Magnesiumstereate 6.00 mg Clear Opadray YS-1-7006 6.25 mg Purified water 0.345 ml

This pharmaceutical composition was used for the aforementioned clinicaltests.

Example 4

A pharmaceutical composition is prepared consisting of 1000 mg ofmetformin hydrochloride and 4 mg of glimepiride, adding the followingexcipients:

Microcrystalline Cellulose PH 101 78.40 mg Coloidal Silica Dioxide 3.60mg Povidone K-90 36.00 mg Croscarmelose Sodium 24.00 mg Magnesiumstereate 6.00 mg Clear Opadray YS-1-7006 6.25 mg Purified water 0.345 ml

This pharmaceutical composition was used for the aforementioned clinicaltests.

1-11. (canceled)
 12. A solid pharmaceutical composition, comprising asynergistic combination of glimepiride and metformin hydrochloride,wherein the weight ratio of glimepiride and metformin hydrochloride isabout 1/250, wherein the combination of glimepiride and metforminhydrochloride reduces blood glucose levels in a patient with type 2diabetes greater than either glimepiride or metformin hydrochloridealone, and wherein the composition further comprises 18 mg to 36 mg ofpovidone, 3 mg to 6 mg of magnesium stearate, and 1.8 mg to 3.6 mg ofcolloidal silicon dioxide.
 13. The solid pharmaceutical compositionaccording to claim 12, comprising 1,000 mg metformin hydrochloride and 4mg glimepiride.
 14. The solid pharmaceutical composition according toclaim 12, comprising 500 mg metformin hydrochloride and 2 mgglimepiride.
 15. A method of controlling blood glucose levels in apatient with type 2 diabetes, comprising administering the compositionof claim 12 to said patient.
 16. The method according to claim 15,comprising administering a composition wherein glimepiride and metforminhydrochloride are present in amounts of 2 mg glimepiride and 500 mgmetformin hydrochloride or 4 mg glimepiride and 1,000 mg metforminhydrochloride.
 17. The method according to claim 15, comprisingadministering a composition wherein glimepiride and metforminhydrochloride are present in amounts of 2 mg glimepiride and 500 mgmetformin hydrochloride.
 18. The method according to claim 15,comprising administering a composition wherein glimepiride and metforminhydrochloride are present in amounts of 4 mg glimepiride and 1,000 mgmetformin hydrochloride.
 19. The solid pharmaceutical compositionaccording to claim 12, wherein the combination of glimepiride andmetformin hydrochloride reduces blood glucose levels in a patient withtype 2 diabetes greater than the additive effect of glimepiride andmetformin hydrochloride alone.
 20. The method according to claim 15,wherein the combination of glimepiride and metformin hydrochloridereduces blood glucose levels in a patient with type 2 diabetes greaterthan the additive effect of glimepiride and metformin hydrochloridealone.
 21. The solid pharmaceutical composition according to claim 12,wherein the combination of glimepiride and metformin hydrochloridereduces glycosylated hemoglobin levels in a patient with type 2 diabetesgreater than either glimepiride or metformin hydrochloride alone. 22.The method according to claim 15, wherein the combination of glimepirideand metformin hydrochloride reduces glycosylated hemoglobin levels in apatient with type 2 diabetes greater than either glimepiride ormetformin hydrochloride alone.
 23. The solid pharmaceutical compositionaccording to claim 21, wherein the combination of glimepiride andmetformin hydrochloride reduces glycosylated hemoglobin levels in apatient with type 2 diabetes greater than the additive effect ofglimepiride and metformin hydrochloride alone.
 24. The method accordingto claim 22, wherein the combination of glimepiride and metforminhydrochloride reduces glycosylated hemoglobin levels in a patient withtype 2 diabetes greater than the additive effect of glimepiride andmetformin hydrochloride alone.
 25. The solid pharmaceutical compositionaccording to claim 12, further comprising microcrystalline cellulose andcroscarmellose sodium.
 26. The solid pharmaceutical compositionaccording to claim 25, further comprising opadry clear.
 27. The solidpharmaceutical composition according to claim 12, further comprising 18mg of povidone, 3 mg of magnesium stearate, and 1.8 mg of colloidalsilicon dioxide.
 28. The solid pharmaceutical composition according toclaim 12, further comprising 36 mg of povidone, 6 mg of magnesiumstearate, and 3.6 mg of colloidal silicon dioxide.
 29. The solidpharmaceutical composition according to claim 13, further comprising 36mg of povidone, 6 mg of magnesium stearate, and 3.6 mg of colloidalsilicon dioxide.
 30. The solid pharmaceutical composition according toclaim 14, further comprising 18 mg of povidone, 3 mg of magnesiumstearate, and 1.8 mg of colloidal silicon dioxide.
 31. The methodaccording to claim 18, wherein the composition further comprises 36 mgof povidone, 6 mg of magnesium stearate, and 3.6 mg of colloidal silicondioxide.